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In vitro Pharmacokinetics/Pharmacodynamics Evaluation of Fosfomycin Combined with Amikacin or Colistin against KPC2-Producing Klebsiella pneumoniae.

ABSTRACT: Objectives: The emergence of carbapenem-resistant Enterobacteriaceae, especially Klebsiella pneumoniae, has become a major concern in clinic settings. Combination therapy is gaining momentum to counter the secondary resistance and potential suboptimal efficacy of monotherapy. The aim of this study was to evaluate the bactericidal effect of fosfomycin (FM), amikacin (AMK), or colistin (COL) alone and combinations against KPC2-producing K. pneumoniae using dynamic model by simulating human pharmacokinetics in vitro. Methods: The Pharmacokinetics Auto Simulation System 400 system was employed to simulate different dosing regimens of FM, AMK, and COL alone and combination. Bacterial growth recovery time (RT) and the area between the control growth and antibacterial killing curves (IE) were used as unbiased and comprehensive means for determining the antimicrobial effect. Results: We observed that COL alone was much pronounced than FM or AMK against KPC-Kp. IE of FM (8 g every 8 h) plus AMK (15 mg/kg once-daily) and FM (8 g every 8 h) plus COL (75,000 IU/kg every 12 h) were higher (>170 and >200 LogCFU/mL·h^-1, respectively) than that of monotherapies against sensitive strains. Of note, the rate of resistance was lower when using the combination of FM (8 g every 8 h) plus COL (75,000 IU/kg every 12 h) than using COL (75,000 IU/kg every 12 h) alone. Conclusions: The combination of FM (8 g every 8 h) plus AMK (15 mg/kg once-daily) and FM (8 g every 8 h) plus COL (75,000 IU/kg every 12 h) were effective at maximizing bacterial killing and suppressing emergence of resistance.

SUBMITTER: Yu W

PROVIDER: S-EPMC5472793 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Synergistic Activity of Colistin/Fosfomycin Combination against Carbapenemase-Producing Klebsiella pneumoniae in an In Vitro Pharmacokinetic/Pharmacodynamic Model.

Project description:Carbapenemase-producing Klebsiella pneumoniae is globally recognized as one of the greatest threats to public health, and combination therapy may be the chemotherapeutic option. In the present study, we aimed to evaluate the antibacterial effects of colistin/fosfomycin combination against carbapenemase-producing K. pneumoniae. The antibacterial effects were determined in a one-compartment in vitro pharmacokinetic model over a period of 24?h. The initial inoculum was 108?CFU/mL. Low, medium, and high Cmax values of colistin at 0.5, 2, and 5?mg/L as well as Cmax of fosfomycin at 100?mg/L were simulated in the model. Doses of both colistin and fosfomycin were given every 8?h until 24?h. For the colistin- and fosfomycin-susceptible isolate KP47, three combination regimens showed greater killing effect compared with colistin monotherapy. The greatest killing effect was observed in combination regimen containing 5?mg/L colistin. For colistin-heteroresistant and fosfomycin-susceptible isolate KP79, combination regimen containing low dose colistin (0.5?mg/L) showed no synergistic or additive effects. However, combination regimens containing 2 and 5?mg/L colistin maintained the bactericidal effect until 24?h compared with colistin monotherapy. For colistin-heteroresistant and fosfomycin-resistant isolates KP42 and KP11, bactericidal activity was barely enhanced by combination regimens. Moreover, combination regimen containing 5?mg/L colistin could only prevent the emergence of colistin-resistant subpopulation in colistin and fosfomycin-susceptible isolate. It is necessary to know the resistant patterns of the K. pneumoniae before using combination of colistin and fosfomycin in clinical practice.

| S-EPMC5937563 | biostudies-literature

Synergetic Effects of Combined Treatment of Colistin With Meropenem or Amikacin on Carbapenem-Resistant Klebsiella pneumoniae in vitro.

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| S-EPMC6916149 | biostudies-literature

Colistin Heteroresistance among Extended Spectrum ?-lactamases-Producing Klebsiella pneumoniae.

Project description:Colistin-heteroresistant (CST-HR) Enterobacterales isolates have been identified recently, challenging the clinical laboratories since routine susceptibility tests fail to detect this phenotype. In this work we describe the first CST-HR phenotype in extended-spectrum ?-lactamase (ESBL)-producing Klebsiella pneumoniae isolates in South America. Additionally, we determine the genomic mechanisms of colistin heteroresistance in these strains. The CST-HR phenotype was analyzed by the population analysis profile (PAP) method, and mutations associated with this phenotype were determined by whole-genome sequencing (WGS) and the local BLAST+ DB tool. As a result, 8/60 isolates were classified as CST-HR according to the PAP method. From WGS, we determined that the CST-HR isolates belong to three different Sequence Types (STs) and four K-loci: ST11 (KL15 and KL81), ST25 (KL2), and ST1161 (KL19). We identified diverse mutations in the two-component regulatory systems PmrAB and PhoPQ, as well as a disruption of the mgrB global regulator mediated by IS1-like and IS-5-like elements, which could confer resistance to CST in CST-HR and ESBL-producing isolates. These are the first descriptions in Chile of CST-HR in ESBL-producing K. pneumoniae isolates. The emergence of these isolates could have a major impact on the effectiveness of colistin as a "last resort" against these isolates, thus jeopardizing current antibiotic alternatives; therefore, it is important to consider the epidemiology of the CST-HR phenotype.

| S-EPMC7569871 | biostudies-literature

In vitro antibacterial effect of fosfomycin combination therapy against colistin-resistant Klebsiella pneumoniae.

Project description:Objectives:Colistin is still a "last-resort" antibiotic used to manage human infections due to multidrug-resistant (MDR) Klebsiella pneumoniae. However, colistin-resistant K. pneumoniae (CR-Kp) isolates emerged a decade ago and had a worldwide distribution. The purpose of this study was to evaluate the genetic data of CR-Kp and identify the antibacterial activity of fosfomycin (FM) alone and in combination with amikacin (AMK) or colistin (COL) against CR-Kp in vitro. Methods:Three clinical CR-Kp isolates from three patients were collected. Whole-genome sequencing and bioinformatics analysis were performed. The Pharmacokinetics Auto Simulation System 400, by simulating human pharmacokinetics in vitro, was employed to simulate FM, AMK, and COL alone and in combination. Different pharmacodynamic parameters were calculated for determining the antimicrobial effect. Results:Whole-genome sequencing revealed that none of the three isolates contain mcr gene and that no insertion was found in pmrAB, phoPQ, or mgrB genes. We found the antibacterial activity of AMK alone was more efficient than FM or COL against CR-Kp. The area between the control growth and antibacterial killing curves of FM (8 g every 8 hours) combined with AMK (15 mg/kg once daily) was higher than 170 LogCFU/mL·h-1. In addition, the area between the control growth and antibacterial killing curves of FM (8 g every 8 hours) combined with COL (75,000 IU/kg every12 hours) was higher than that of monotherapies (>100 LogCFU/mL·h-1 vs <80 LogCFU/mL·h-1). Conclusion:FM (8 g every 8 hours) combined with AMK (15 mg/kg once daily) was effective at maximizing bacterial killing against CR-Kp.

| S-EPMC5926077 | biostudies-literature

Elucidating the Pharmacokinetics/Pharmacodynamics of Aerosolized Colistin against Multidrug-Resistant Acinetobacter baumannii and Klebsiella pneumoniae in a Mouse Lung Infection Model.

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| S-EPMC5786800 | biostudies-other

mcr-1 Colistin Resistance in ESBL-Producing Klebsiella pneumoniae, France.

Project description:We report intestinal carriage of an extended-spectrum β-lactamase-producing Klebsiella pneumoniae strain with high-level resistance to colistin (MIC 24 mg/L) in a patient in France who had been hospitalized for fungal meningitis. The strain had the mcr-1 plasmid gene and an inactivated mgrB gene, which are associated with colistin resistance.

| S-EPMC5403025 | biostudies-literature

Evaluation of the Synergy of Ceftazidime-Avibactam in Combination with Meropenem, Amikacin, Aztreonam, Colistin, or Fosfomycin against Well-Characterized Multidrug-Resistant Klebsiella pneumoniae and Pseudomonas aeruginosa.

Project description:Multidrug-resistant (MDR) Gram-negative organisms are a major health concern due to lack of effective therapy. Emergence of resistance to newer agents like ceftazidime-avibactam (CZA) further magnifies the problem. In this context, combination therapy of CZA with other antimicrobials may have potential in treating these pathogens. Unfortunately, there are limited data regarding these combinations. Therefore, the objective of this study was to evaluate CZA in combination with amikacin (AMK), aztreonam (AZT), colistin (COL), fosfomycin (FOS), and meropenem (MEM) against 21 carbapenem-resistant Klebsiella pneumoniae and 21 MDR Pseudomonas aeruginosa strains. The potential for synergy was evaluated via MIC combination evaluation and time-kill assays. All strains were further characterized by whole-genome sequencing, quantitative real-time PCR, and SDS-PAGE analysis to determine potential mechanisms of resistance. Compared to CZA alone, we observed a 4-fold decrease in CZA MICs for a majority of K. pneumoniae strains and at least a 2-fold decrease for most P. aeruginosa isolates in the majority of combinations tested. In both P. aeruginosa and K. pneumoniae strains, CZA in combination with AMK or AZT was synergistic (≥2.15-log10 CFU/ml decrease). CZA-MEM was effective against P. aeruginosa and CZA-FOS was effective against K. pneumoniae Time-kill analysis also revealed that the synergy of CZA with MEM or AZT may be due to the previously reported restoration of MEM or AZT activity against these organisms. Our findings show that CZA in combination with these antibiotics has potential for therapeutic options in difficult to treat pathogens. Further evaluation of these combinations is warranted.

| S-EPMC6658738 | biostudies-literature

Evaluation of ceftazidime/avibactam alone and in combination with amikacin, colistin and tigecycline against Klebsiella pneumoniae carbapenemase-producing K. pneumoniae by in vitro time-kill experiment.

Project description:Klebsiella pneumoniae carbapenemase-producing K. pneumoniae (KPC-Kp) poses a major threat to human health worldwide. Combination therapies of antibiotics with different mechanisms have been recommended in literatures. This study assessed in vitro antibacterial activities and synergistic activities of ceftazidime/avibactam alone and in combinations against KPC-Kp. In total, 70 isolates from 2 hospitals in Beijing were examined in our study. By using the agar dilution method and broth dilution method, we determined the minimum inhibitory concentration (MIC) of candidate antibiotics. Ceftazidime/avibactam demonstrated promising susceptibility against KPC-Kp (97.14%). Synergistic activities testing was achieved by checkerboard method and found ceftazidime/avibactam-amikacin displayed synergism in 90% isolates. Ceftazidime/avibactam-colistin displayed partial synergistic in 43% isolates, and ceftazidime/avibactam-tigecycline displayed indifference in 67% isolates. In time-kill assays, antibiotics at 1-fold MIC were mixed with bacteria at 1 × 105 CFU/ml and Mueller-Hinton broth (MHB). Combinations of ceftazidime/avibactam with amikacin and tigecycline displayed better antibacterial effects than single drug. Ceftazidime/avibactam-colistin combination did not exhibit better effect than single drug. In KPC-Kp infections, susceptibility testing suggested that ceftazidime/avibactam may be considered as first-line choice. However, monotherapy is often inadequate in infection management. Thus, our study revealed that combination therapy including ceftazidime/avibactam colistin and ceftazidime/avibactam tigecycline may benefit than monotherapy in KPC-Kp treatment. Further pharmacokinetic/pharmacodynamic and mutant prevention concentration studies should be performed to optimize multidrug-regimens.

| S-EPMC8516195 | biostudies-literature

Pharmacodynamics of Aerosolized Fosfomycin and Amikacin against Resistant Clinical Isolates of Pseudomonas aeruginosa and Klebsiella pneumoniae in a Hollow-Fiber Infection Model: Experimental Basis for Combination Therapy.

Project description:There has been a resurgence of interest in aerosolization of antibiotics for treatment of patients with severe pneumonia caused by multidrug-resistant pathogens. A combination formulation of amikacin-fosfomycin is currently undergoing clinical testing although the exposure-response relationships of these drugs have not been fully characterized. The aim of this study was to describe the individual and combined antibacterial effects of simulated epithelial lining fluid exposures of aerosolized amikacin and fosfomycin against resistant clinical isolates of Pseudomonas aeruginosa (MICs of 16 mg/liter and 64 mg/liter) and Klebsiella pneumoniae (MICs of 2 mg/liter and 64 mg/liter) using a dynamic hollow-fiber infection model over 7 days. Targeted peak concentrations of 300 mg/liter amikacin and/or 1,200 mg/liter fosfomycin as a 12-hourly dosing regimens were used. Quantitative cultures were performed to describe changes in concentrations of the total and resistant bacterial populations. The targeted starting inoculum was 108 CFU/ml for both strains. We observed that neither amikacin nor fosfomycin monotherapy was bactericidal against P. aeruginosa while both were associated with rapid amplification of resistant P. aeruginosa strains (about 108 to 109 CFU/ml within 24 to 48 h). For K. pneumoniae, amikacin but not fosfomycin was bactericidal. When both drugs were combined, a rapid killing was observed for P. aeruginosa and K. pneumoniae (6-log kill within 24 h). Furthermore, the combination of amikacin and fosfomycin effectively suppressed growth of resistant strains of P. aeruginosa and K. pneumoniae In conclusion, the combination of amikacin and fosfomycin was effective at maximizing bacterial killing and suppressing emergence of resistance against these clinical isolates.

| S-EPMC5192115 | biostudies-literature

Structural modification of LPS in colistin-resistant, KPC-producing Klebsiella pneumoniae.

Project description:BackgroundColistin resistance in Klebsiella pneumoniae typically involves inactivation or mutations of chromosomal genes mgrB, pmrAB or phoPQ, but data regarding consequent modifications of LPS are limited.ObjectivesTo examine the sequences of chromosomal loci implicated in colistin resistance and the respective LPS-derived lipid A profiles using 11 pairs of colistin-susceptible and -resistant KPC-producing K. pneumoniae clinical strains.MethodsThe strains were subjected to high-throughput sequencing with Illumina HiSeq. The mgrB gene was amplified by PCR and sequenced. Lipid profiles were determined using MALDI-TOF MS.ResultsAll patients were treated with colistimethate prior to the isolation of colistin-resistant strains (MIC >2 mg/L). Seven of 11 colistin-resistant strains had deletion or insertional inactivation of mgrB. Three strains, including one with an mgrB deletion, had non-synonymous pmrB mutations associated with colistin resistance. When analysed by MALDI-TOF MS, all colistin-resistant strains generated mass spectra containing ions at m/z 1955 and 1971, consistent with addition of 4-amino-4-deoxy-l-arabinose (Ara4N) to lipid A, whereas only one of the susceptible strains displayed this lipid A phenotype.ConclusionsThe pathway to colistin resistance in K. pneumoniae primarily involves lipid A modification with Ara4N in clinical settings.

| S-EPMC5890713 | biostudies-literature

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